The authentic gene responsible for the development of both retinoblastoma (Rb) and osteosarcoma has recently been cloned within our program. Using cDNA probes of the Rb gene, structural changes (deletions and rearrangements) were observed in 16 of 40 retinoblastomas examined as well as in an osteosarcoma. Whether or not structural aberrations were found, the retinoblastomas and osteosarcomas has either an absence of the Rb transcript or an abnormal transcript. Having cloned the Rb gene and shown that it is the loss or inactivation of both alleles of the Rb gene that is responsible for retinoblastoma and osteosarcoma, our plans include determining in which other cancers the Rb gene has a role in the etiology of the tumor. Prime candidates include: 1. other tumors arising in patients with hereditary retinoblastoma, especially soft tissue sarcomas, 2. alveolar rhabdomyosarcomas, 3. hereditary breast cancer, 4. small cell carcinoma of the lung and 5. melanomas. We shall examine the Rb gene in the tumors mentioned above as well as other tumor types to determine if changes at the structural or RNA level can be identified in a similar manner as retinoblastoma and osteosarcoma. Our group fortunately has access to a unique population of tumor specimens including the largest number of cases with second malignancies in the world who have previously had retinoblastoma. These studies could have extremely important implications in understanding the basis of human cancer and in identifying several other malignancies in which the Rb gene has a key role. We shall also examine whether the Rb gene has an etiological role in additional families who have dominantly inherited predisposition to develop cancer. Finally, we shall examine all known oncogenes for their expression in retinoblastomas, osteosarcomas, and other tumor in which the Rb gene is a causative factor. Methodologies to be used include standard molecular biological and cytogenetic techniques presently available in our laboratory.